The overall goal of this application is to determine the quantitative characteristics of in vivo SHIV replication in the Rhesus Macaque, as a model of human HIV-1 infection. Since viral replication occurs in lymphoid tissue, which is extremely difficult to obtain in a clinical setting, the focus is on detailed analysis of viral and cellular dynamics in multiple lymphoid tissues obtained at necropsy from infected non-human primates. The first hypothesis is that different lymphoid tissues (lymph nodes, spleen, and intestine) have unique quantitative patterns of SHIV replication. We will determine the quantitative contribution of viral replication in these compartments to the total body load of virus, as reflected with the plasma SHIV RNA. The second hypothesis is that the lineage of cells that support SHIV replication is distinctive, with infected macrophages (Mphi) supporting chronic infection that generates a higher frequency of infected T cells in the local histologic microenvironment. The third hypothesis is that a population of latently infected T cells exists in SHIV infection and contributes to persistent viral replication in animals treated with antiretroviral drugs. Each of these hypotheses will be critically examined in SHIV infected animals in three distinct stages of infection: 1) steady state infection, 2) acute infection, and 3) the response to a powerful antiretroviral agent PMPA. The approach is to perform a multiparameter analysis of in vivo viral and cellular dynamics in multiple tissue compartments. Specimens of blood, spleen, thymus, all available lymph nodes, multiple portions of gut, bone marrow, lung, liver, and brain will be examined by a standard set of quantitative analyses.